DECREASED EXPRESSION AND ACTIVITY OF P-GLYCOPROTEIN IN RAT-LIVER DURING ACUTE-INFLAMMATION

Purpose. Drug disposition is often altered in inflammatory disease. Al though the influence of inflammation on hepatic drug metabolism and pr otein binding has been well studied, its impact on drug transport has largely been overlooked. The multidrug resistance (MDR) gene product, P-glycoprotein (P-gp) is involved in the active secretion of a large v ariety of drugs. Our goal was to ascertain the influence of acute infl ammation (AI) on the expression and functional activity of P-gp. Metho ds. AI was induced in rats through turpentine or lipopolysaccharide (L PS) administration. Expression of P-gp in liver was detected at the le vel of protein on Western blots using the monoclonal antibody C-219 an d at the level of mRNA using an RNase protection assay. P-gp mediated transport activity was assessed by measuring the verapamil-inhibitable efflux of rhodamine 123 (R123) in freshly isolated hepatocytes. Resul ts. Turpentine-induced Al significantly decreased the hepatic protein expression of P-gp isoforms by 50-70% and caused a significant 45-55% reduction in the P-gp mediated efflux of R123. Diminished mRNA levels of all three MDR isoforms were seen. LPS-induced AI similarly resulted in significantly reduced levels and activity of P-gp in liver. Althou gh differences in the constitutive levels of P-gp were seen between ma le and female rats, the influence of AI on P-gp expression and activit y was not gender specific. Conclusions, Experimentally-induced inflamm ation decreases the in vivo expression and activity of P-gp in liver. This is the first evidence that expression of P-gp is modulated in res ponse to experimentally-induced inflammation.